Other HIV PrEP studies at CROI 2015: implementation of oral PrEP and problems with tenofovir gel
Simon Collins, HIV i-Base
Although the headline PrEP news at CROI 2015 went to the PROUD and IPERGAY studies (see reports above), important additional PrEP trials covered implementation and alternative dosing with oral PrEP and disappointing news that tenofovir gel was not effective in African women.
Raphael Landovitz set the context for the meeting in a plenary lecture about oral PrEP including implementation scale-up, especially the initially low but now increasing uptake in the US. 
This included reference to the difference pharmacokinetics of tenofovir and FTC with 10-100 fold higher tenofovir exposures in rectal compared to cervico-vaginal tissue. This suggests that the adherence requirement may be higher for women (6/7 doses/week) compared to men (when >4 doses/week still confers high level protection).
Referring to the heat map modelling by Abbas et al showed that the population effect on reducing infections seen in high effectiveness studies is not reduced even if risk behaviour increases,  noting the risk compensation has not been reported from randomised PrEP trials, including in open-label studies.
Also drug resistance has generally been rare (~2% of infected, 0.06% of exposed) in studies with frequent clinic attendance, this is due to either sufficiently high adherence to protect against infection or sufficiently low adherence to not provide selective pressure. As expanded access to PrEP involves less frequent HIV testing in real life settings, monitoring is warranted for the higher risk of resistance from continuing (or returning) to use PrEP after occult HIV infection and prior to diagnoses (~25%).
The time for daily dosing to reach protective levels has been estimated as needing five days for men to reach 99% protection for rectal exposure (95% CI: 69% to 100%) and that after reaching steady state, protection might be maintained (in men) at >90% for seven days, but dramatically drops thereafter. 
In contrast, it is likely to take three weeks of daily dosing for women to reaching estimated protective levels.
Although side effect reports have been low in clinical studies, this is also in the context of low adherence and therefore much lower actual drug exposure.
This talk noted the tremendous potential for PrEP to become new options that HIV negative people can use to take control of their protection against HIV.
PrEP as a bridge to ART in serodifferent couples
Jared Baeten from the University of Washington, presented important results from using short-term PrEP as a “bridge” by HIV negative partners in serodifferent couples until the HIV positive partner started ART, and for six months (or longer) after. 
The Partners Demonstration Project enrolled more than 1000 serodifferent high risk heterosexual couples in Kenya and Uganda between November 2012 and August 2014. Based on a population incidence of 5.3/100 person-years (95% CI: 3.2 to 7.6), approximately 20 new infections were expected.
However, up until July 2014, only one incident HIV infection was reported from 440 person-years of follow-up. This was an observed HIV incidence of 0.2/100 person-years (95% CI: 0.0 to 1.3), p<0.0001 vs predicted. During the 440 person-years of follow-up, PrEP was used 47% of the time, ART 17%, both 25%, and neither 11%.
The single transmission occurred with evidence of low PrEP adherence and in the absence of ART.
The potential benefit from PrEP as a bridge during the first six months of ART was also reported in a poster from the Partners PrEP study, based on transmission risks during three periods: (1) after diagnosis while eligible for ART but not on ART; (2) during the first six months that the positive partner was on ART; and (3) when the positive partner had been on ART for >6 months. 
During 510 person-years of follow-up for negative partners in periods 1, (175 PY), 2 (168 PY) and 3 (167 PY), there were 3 phylogenetically linked HIV infections in each of groups 1 and 2 and no HIV infections in group 3. The numbers of sex acts was roughly comparable between groups, as was the generally high reported use of condoms (~90-92% of times).
HIV incidence (95% CI) was 1.71 (0.35 to 5.01), 1.79 (0.37 to 5.22) and 0.00 (0.00 to 2.20) per 100 person-years, in groups 1, 2 and 3, respectively.
Details were not provided on whether unlinked infections occurred, although PrEP in the pre-ART and early ART periods would also provide protection from other partners.
PrEP as public health strategy to reduce new infections in San Francisco
Robert Grant, from University of California San Francisco, provided an update on the recent use of PrEP in San Francisco and the potential impact on population rates of HIV transmission that included modeling data for reducing rates by 70%. 
Based on 2014 data, 94% of HIV positive people in San Francisco are diagnosed, 88%-91% are on (or have used) ART, 88% of those in care and 62% overall are virally suppressed. These rates have been stable for three years and PrEP use started to increase in 2013. From 2007 to 2013, annual diagnoses fell from 515 to 359 and HIV-related mortality fell from 515 to 359 and from 323 to 182.
Using public health data, population survey and results from clinical studies, the group modelled targets for future programmes. Of the estimated 50,000 HIV negative gay men in the city, approximately one third (16,000) were thought eligible for PrEP based on not using condoms with two or more recent partners), and a third of these (5000 men) had used PrEP in the previous 12 months. PrEP use positively correlated with risk, with 63% of men in one survey reporting recent condomless sex having used PrEP.
The impact of PrEP was based on data from iPrEX-OLE, that reported 81% continued use of PrEP after 12 months, of whom 92% were adherent with >4 doses a week.
Modelling looked at PrEP uptake by 95% of those at risk achieved 70% reduction in expected new infections (to 125 a year), with 14,000 follow up years of PrEP use. Modelling greater roll out of treatment (from current 62% to target 90%) had additive benefits to bring annual diagnoses numbers to 100/year.
Greater real-life coverage from daily vs alternative dosing in African women
The HPTN 067 ADAPT is an international study that was testing alternative dosing strategies for oral PrEP in the US, Thailand and South Africa. The full study includes MSM, transgender women and women who have sex with men who are at high risk of HIV. Results from the South African cohort of 191 African women in Cape Town were presented at CROI 2015 as a late breaker poster. [7, 8]
The study design include a five-week lead-in phase when all participants were prescribed daily oral PrEP, with one weekly dose being directly observed therapy (DOT) at the clinic. PrEP was not taken during week five, to assess drug levels and PK in plasma, BPMCs and hair samples (also collected at weeks 10 and 30). At week six, participants were randomised to one of three unblinded self-administered dosing groups, and followed for 24 weeks.
- Continuing daily PrEP (D).
- Twice-weekly PrEP plus a post-intercourse dose (T).
- By exposure – taking PrEP before and after sex (E).
Behaviour/risk exposures were based on weekly telephone interviews. All participants also receive counselling for adherence support, risk reduction and condom advice plus free condoms and lube at baseline and throughout the study.
The study hypothesis was that non-daily PrEP would lead to greater overall protection with fewer side effects. To assess this, drug coverage was defined as >1 pill in the 4 days before and >1 pill taken in the 24 hours after sexual intercourse and adherence was defined as the percentage of pills taken (monitored by an electronic pill box).
Of 294 women screened in Cape Town, 7 (6.8%) were HIV positive (using a rapid test), 191 were enrolled, and 179 were randomized at week six (there were two further HIV positive results). Participants were generally young (median age 26 years, range 18-52), single (80% were unmarried) and not employed (83% unemployed).
Results were presented for each strategy at week 30. Over follow-up, there were significant differences in levels of sexual activity with approximately 2000, 1000 and 1500 events in the D, T and E groups, respectively (p=0.002). Daily PrEP as a strategy resulted in significantly greater drug coverage of events (75%, 56% and 52%) and adherence (76%, 65% and 53%) D, T and E groups, respectively (p<0.001). Drug levels at weeks 10 and 30 were also significantly higher with daily PrEP (p=0.03 in plasma and 0.006 in PBMCs) although levels also dropped in all three groups by the end of the study, see Table1.
Although it was not a study endpoint, there was no significant difference in new infections between the strategies, (1, 2 and 2 in the D, T and E groups respectively), although it is unclear if this was adjusted for numbers of exposures and/or PrEP coverage.
|Daily (D)||Twice-weekly-plus (T)||Pre-/post-sex (E)||p-value (across 3 groups)|
|HIV infections||1||2||2||0.87 NS|
|No. of times people had sex (events)||1954||1078||1533||0.002|
|New HIV infections||1||2||2||NS|
|% events fully covered||75||56||52||<0.001|
|% of events partially covered (pre-only, post-only)||22(21, 1)||39(30, 9)||41(33, 8)||<0.001|
|% events not covered||3||6||7||NA|
|Total pills needed||9758||3629||2295||<0.001|
|Total pills used||7441||2850||2002||<0.001|
|Total % adherence||76||65||53||<0.001|
|% detectable in plasma (if sex in prior 7 days): at weeks 10, 30||92, 79||86, 62||80, 53||0.03|
|% >9.1 fmol/106 target in PBMC: at weeks 10, 30||80, 65||50, 46||57, 32||0.006|
Tenofovir gel fails to show efficacy in FACTS 001 study in South African women
Results from the randomised, double-blind, placebo-controlled Phase 3 study FACTS 001 study reported low efficacy of 1% tenofovir gel used pericoitally in 2059 young women (median age 23, IQR: 20 to 25) at nine rural and urban clinics in South Africa. 
As low adherence in the VOICE study had failed to show a protective benefit from daily use of the same gel, FACTS 001 included a specific focus on adherence.
The gel was provided in single-applicators and the dosing strategy involved a pre-dose (up to 12 hours before sex) and post dose (up to 12 hours after sex), with no more than one dose in any 24 hour period.
This was an endpoint-driven study requiring 118 new HIV infections, powered to show 45% efficacy with an HIV incidence rate of 3.5/100 PY and allowing for 13% loss to follow up.
After approximately 3035 person years of follow up, there were 61 vs 62 infections in the gel vs placebo groups respectively, with the same incidence rate in each arm (4.0 per 100 PYFU; 95% CI: 3.1 to 5.2) and an Incidence Rate Ratio of 1.0 (95% CI: 0.7 to 1.4).
Several analyses were presented for whether this outcome was related to adherence or product effectiveness (given that positive results were reported in the CAPRISA 004 study).
Based on returned applicators, average adherence was reported as 75% overall, with participants using the gel for 50-60% of the time in both group. Only 13% of women were categorised as being highly adherent based on using the gel >80% of the times they had sex.
A nested case control study of participants in the tenofovir arm (56 cases, 158 controls) tested for tenofovir drug levels in quarterly cervical-vaginal lavage samples (1075 samples, median 5 (range 1-11) per person). Overall, 22% women had detectable levels at all visits, 65% at some, and 13% at no visits.
Importantly, detectable tenofovir levels were significantly associated with 52% reduction in HIV risk (aHR 0.48; 95% CI: 0.23 to 0.97, p=0.04).
As comment, the conclusion emphasised that the study results showed that participants had actively engaged with this intervention but that better products were needed in order for women to be able to achieve sufficient protective drug levels.
Unless stated otherwise, all references are to the Programme and Abstracts of the 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle, Washington, USA.
- Landovitz RJ. PrEP for HIV prevention: what we know and what we still need to know for implementation. Plenary lecture PL1. CROI 2015, 23-26 February, Seattle. Oral abstract 20.
- Abbas UL et al. Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings. (19 September 2007). PLoS ONE 2(9): e875. doi:10.1371/journal.pone.0000875.
- Seifert SM et al. Dose response for starting and stopping HIV preexposure prophylaxis for men who have sex with men. Clin Infect Dis. (2015) 60 (5): 804-810. Published online: 18 November 2014. doi: 10.1093/cid/ciu916.
- Baeten J et al. Near elimination of HIV transmission in a demonstration project of PrEP and ART. CROI 2015, 23-26 February, Seattle. Oral abs 24.
- Abstract: Mujugira A et al. HIV-1 transmission risk persists during the first 6 months of antiretroviral therapy. CROI 2015, 23-26 February, Seattle. Poster abstract 989.
Poster: http://www.croiconference.org/sites/default/files/posters-2015/989.pdf (PDF)
- Grant RM et al. Scale-up of preexposure prophylaxis in San Francisco to impact HIV incidence. CROI 2015, 23-26 February, Seattle. Oral abstract 25.
- Bekker L-G et al. HPTN 067/ADAPT Cape Town: A comparison of daily and nondaily PrEP dosing in African women. CROI 2015, 23-26 February, Seattle. Late breaker poster abstract 978LB.
Poster: http://www.croiconference.org/sites/default/files/posters-2015/978LB.pdf (PDF)
- HPTN 067 ADAPT study website.
- Rees H et al. FACTS 001 Phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. CROI 2015, 23-26 February, Seattle. Oral late breaker abstract 26LB.